Amine derivative

ABSTRACT

The invention relates to (1S)-1-isobutoxymethyl-3-methylbutylamine useful as an intermediate in the synthesis of sodium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate and a process for production thereof. The process comprises reacting L-leucinol with a compound represented by the following formula in the presence of a base and reducing the obtained (1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutyl-amine:  
                 
[in which X is a leaving group].

FIELD OF THE INVENTION

The present invention relates to an amine derivative and a process ofproduction thereof.

BACKGROUND OF THE INVENTION

The under-illustrated sodium(2S,3S)-3-[[(1S)-1-iso-butoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate(hereinafter referred to as Compound A) shows a cathepsin-inhibitoryaction and is useful as a remedy for treating rheumatoid arthritis andosteoporosis (Patent reference 1: WO 99/11640 pamphlet):

Patent reference 1 describes a process for producing Compound Aaccording to the following reaction scheme (see Example 48 of Patentreference 1):

There is a need to provide an industrially employable synthesis processfor the production of Compound A.

DISCLOSURE OF THE INVENTION

The present invention has an object to provide an amine derivativeemployable as an intermediate compound for the synthesis of Compound A.The amine derivative is (1S)-1-isobutoxymethyl-3-methylbutylaminerepresented by the following formula:

The invention also has an object to provide a process for producing theamine derivative.

The (1S)-1-isobutoxymethyl-3-methylbutylamine can be obtained accordingto the following reaction scheme:

Step 1: L-leucinol (2)→Compound (3)

The reaction of L-leucinol (2) with the compound (4) can be performed insuch a solvent not participating in the reaction as THF or DMSO at atemperature between −30° C. and the reflux temperature in the presenceof a base.

Examples of the leaving groups represented by X in the compound (4)include halogens such as chlorine, bromine and iodine,p-toluenesulfonyloxy, and methanesulfonyloxy.

Examples of the bases include alkali metal hydrides such as NaH, LiH andKH, alkaline earth metal hydrides such as CaH₂, alkali metal alkoxidessuch as t-BuOK, inorganic bases such as NaOH and KOH, and organic basessuch as triethylamine

The starting compound, namely L-leucinol, can be obtained by reducingL-leucine (for example, U.S. Pat. No. 3,935,280).

Step 2: Compound (3)→Compound (1)

The reaction can be performed in such a solvent not participating in thereaction as ethanol or acetic acid at a hydrogen pressure of 1 to 100atm., using 0.1 to 20% of such a catalyst employable for catalyticreduction of a double bond as Pd/C or Raney nickel.

The (1S)-1-isobutoxymethyl-3-methybutylamine also can be producedaccording to the following reaction scheme:

[in which X has the same leaving group as above].

The aforementioned Compound A can be produced from the(1S)-1-isobutoxymethyl-3-methylbutylamine obtained above according tothe following reaction scheme (see Examples 48 and 18a of Patentreference 1):

The process of the invention can give the amine derivative, i.e.,(1S)-1-isobutoxymethyl-3-methylbutyl-amine, in a high yield. Theaforementioned Compound A can be obtained from this amine derivative ina high yield.

The invention is further described by the following examples.

EXAMPLE 1 (1S)-1-(2-methyl-2-propenoxymethyl)-3-methyl-butylamine

To a solution of L-leucinol (20.0 g, 0.17 mol) in an anhydrous THF (200mL) was portionwise added 60% NaH (7.92 g, 0.198 mol). The resultingmixture was stirred for 30 min. at room temperature and further for 2hours at 50° C. The mixture was then cooled to room temperature. To theresulting suspension was dropwise added a solution of3-chloro-2-methylpropene (15.45 g, 0.17 mol) in an anhydrous THF (50mL). The resulting mixture was stirred for 20 hours at room temperature.The THF was distilled off under reduced pressure. To the residue weresuccessively added a mixture of ice and water and diethyl ether. Themixture was stirred for 5 min. at room temperature, and the organicportion was separated. The aqueous portion was subjected to extractionwith diethyl ether. The extract was combined with the organic portion.The combined organic portion was washed with 1 mol/L aqueoushydrochloric acid (7 mL) and subjected to extraction with 1 mol/Laqueous hydrochloric acid (153 mL). The resulting hydrochloric acidextract was made to approx. pH 10 by addition of potassium carbonate andsubjected to extraction with diethyl ether. The organic portion waswashed with water, dried over sodium sulfate, and placed under reducedpressure to distill the solvent off. There was obtained the titledcompound (20.22 g, 69.2%) as an oily product.

¹H-NMR (CDCl₃) δ: 0.90 (3H, d, J=7 Hz), 0.93 (3H, d, J=7 Hz), 1.1-1.3(2H, m), 1.74 (3H, s), 1.7-1.8 (1H, m), 2.62 (2H, broad s), 3.0-3.1 (1H,m), 3.15 (1H, dd, J=8 Hz & 9 Hz), 3.38 (1H, dd, J=3 Hz & 9 Hz), 3.88(1H, d, J=13 Hz), 3.92 (1H, d, J=13 Hz), 4.89 (1H, s), 4.96 (1H, s).

EXAMPLE 2 (1S)-1-Isobutoxymethyl-3-methylbutylamine

A suspension of (1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutylamine(51.9 g, 0.3 mol) and 5% Pd/C (10.4 g) in ethanol (520 mL) was stirredfor 18 hours at room temperature in a hydrogen atmosphere (1 atm.). Tothe resulting reaction mixture was added 6 mol/L aqueous hydrochloricacid (52 mL) under cooling in ice bath. The aqueous mixture wassubjected to filtration using celite for removing insolubles and thenplaced under reduced pressure for distilling the solvent off. Theresidue was dissolved in water, and the resulting aqueous solution wasmade to approx. pH 10 by addition of potassium carbonate. The solutionwas subjected to extraction with diethyl ether. The organic portion wasdried over sodium sulfate and placed under reduced pressure fordistilling off the solvent. There was obtained the titled compound (48.6g, 92.6%) as an oily compound.

bp: 66-67° C./5 mg

¹H-NMR (CDCl₃) δ: 0.90 (3H, d, J=6 Hz), 0.90 (3H, d, J=6 Hz), 0.91 (3H,d, J=6 Hz), 0.93 (3H, d, J=6 Hz), 1.1-1.2 (2H, m), 1.50 (2H, broad s),1.6-1.8 (1H, m), 1.8-1.9 (1H, m), 3.0-3.1 (1H, m), 3.11 (1H, dd, J=8 Hz& 9 Hz), 3.16 (1H, dd, J=7 Hz & 9 Hz), 3.23 (1H, dd, J=7 Hz & 9 Hz),3.37 (1H, dd, J=3 Hz & 9 Hz).

1. (1S)-1-Isobutoxymethyl-3-methybutylamine.
 2. A process for preparing(1S)-1-isobutoxymethyl-3-methybutylamine which comprises reducing(1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutylamine.
 3. A process forpreparing (1S)-1-isobutoxymethyl-3-methylbutylamine which comprises thesteps of: reacting L-leucinol and a compound having the followingformula:

in which X is a leaving group, in the presence of a base, to give a(1S)-1-(2-methyl-2-propenoxymethyl)-3 -methylbutylamine, and reducingthe (1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutylamine.